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Activation of notch 3/c-MYC/CHOP axis regulates apoptosis and promotes sensitivity of lung cancer cells to mTOR inhibitor everolimus
Li,Ting1; Xu,Xiao Huang1; Guo,Xia1; Yuan,Tao2; Tang,Zheng Hai1; Jiang,Xiao Ming1; Xu,Yu Lian1; Zhang,Le Le1; Chen,Xiuping1; Zhu,Hong2; Shi,Jia Jie1; Lu,Jin Jian1
2020-05-01
Source PublicationBiochemical Pharmacology
ISSN0006-2952
Volume175
Abstract

The mammalian target of rapamycin (mTOR) pathway converges diverse environmental cues to support the lung cancer growth and survival. However, the mTOR-targeted mono-therapy does not achieve expected therapeutic effect. Here, we revealed that fangchinoline (FCL), an active alkaloid that purified from the traditional Chinese medicine Stephania tetrandra S. Moore, enhanced the anti-lung cancer effect of mTOR inhibitor everolimus (EVE). The combination of EVE and FCL was effective to activate Notch 3, and subsequently evoked its downstream target c-MYC. The blockage of Notch 3 signal by the molecular inhibitor of γ-secretase or siRNA of Notch 3 reduced the c-MYC expression and attenuated the combinational efficacy of EVE and FCL on cell apoptosis and proliferation. Moreover, the c-MYC could bind to the C/EBP homologous protein (CHOP) promoter and facilitate CHOP transcription. The conditional genetic deletion of CHOP reduced the apoptosis on lung cancer cells to the same degree as blockage of Notch 3/c-MYC axis, providing further evidence for that the Notch 3/c-MYC axis regulates the transcription of CHOP and finally induces apoptosis upon co-treatment of FCL and EVE in lung cancer cells. Overall, our findings, to the best of our knowledge, firstly link CHOP to Notch 3/c-MYC axis-dependent apoptosis and provide the Notch 3/c-MYC/CHOP activation as a promising strategy for mTOR-targeted combination therapy in lung cancer treatment.

KeywordApoptosis C-myc Chop Lung Cancer Notch 3
DOI10.1016/j.bcp.2020.113921
URLView the original
Indexed BySCIE
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000527350300040
Scopus ID2-s2.0-85082412875
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Cited Times [WOS]:4   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Corresponding AuthorLu,Jin Jian
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macau,Macao,China
2.Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,310058,China
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Li,Ting,Xu,Xiao Huang,Guo,Xia,et al. Activation of notch 3/c-MYC/CHOP axis regulates apoptosis and promotes sensitivity of lung cancer cells to mTOR inhibitor everolimus[J]. Biochemical Pharmacology,2020,175.
APA Li,Ting,Xu,Xiao Huang,Guo,Xia,Yuan,Tao,Tang,Zheng Hai,Jiang,Xiao Ming,Xu,Yu Lian,Zhang,Le Le,Chen,Xiuping,Zhu,Hong,Shi,Jia Jie,&Lu,Jin Jian.(2020).Activation of notch 3/c-MYC/CHOP axis regulates apoptosis and promotes sensitivity of lung cancer cells to mTOR inhibitor everolimus.Biochemical Pharmacology,175.
MLA Li,Ting,et al."Activation of notch 3/c-MYC/CHOP axis regulates apoptosis and promotes sensitivity of lung cancer cells to mTOR inhibitor everolimus".Biochemical Pharmacology 175(2020).
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